Integrative Metallomics Studies of Toxic Metal(loid) Substances at the Blood Plasma–Red Blood Cell–Organ/Tumor Nexus

Abstract

Globally, an estimated 9 million deaths per year are caused by human exposure to environmental pollutants, including toxic metal(loid) species. Since pollution is underestimated in calculations of the global burden of disease, the actual number of pollution-related deaths per year is likely to be substantially greater. Conversely, anticancer metallodrugs are deliberately administered to cancer patients, but their often dose-limiting severe adverse side-effects necessitate the urgent development of more effective metallodrugs that offer fewer off-target effects. What these seemingly unrelated events have in common is our limited understanding of what happens when each of these toxic metal(loid) substances enter the human bloodstream. However, the bioinorganic chemistry that unfolds at the plasma/red blood cell interface is directly implicated in mediating organ/tumor damage and, therefore, is of immediate toxicological and pharmacological relevance. This perspective will provide a brief synopsis of the bioinorganic chemistry of AsIII, Cd2+, Hg2+, CH3Hg+ and the anticancer metallodrug cisplatin in the bloodstream. Probing these processes at near-physiological conditions and integrating the results with biochemical events within organs and/or tumors has the potential to causally link chronic human exposure to toxic metal(loid) species with disease etiology and to translate more novel anticancer metal complexes to clinical studies, which will significantly improve human health in the 21st century.